Abstract: Brain MRI of human glaucoma Primary open angle glaucoma (POAG) is a leading cause of blindness, affecting 4 million Americans. The disease starts with loss of peripheral vision followed by central vision. While elevated intraocular pressure is thought to be a critical pathogenic mechanism causing retinal ganglion cell death, many glaucoma patients continue to lose vision despite successful treatment to lower intraocular pressure. Here, we pursue a novel hypothesis that pathological changes to the brain also occur in glaucoma, contributing to disease pathogenesis and progression. This hypothesis is based on our preliminary fMRI data showing that mild to moderate POAG patients have functional remapping in the visual cortex. These preliminary fMRI data also show changes vary not only as a function of peripheral to central visual field but also as a function of disease severity. Further, these functional changes have structural correlates of gray- and white-matter degeneration in the brain visual pathways. More effective treatment for glaucoma may require comprehensive strategies that target both the eye and the brain. Our findings agree with prior histological evidence of concurrent neurodegeneration in the brain visual pathway in glaucoma. In fact, some studies even show that structural damage in the brain visual pathway precedes the loss of retinal ganglion cell fibers, suggesting neurodegeneration plays a role in this blinding disorder. A few prior fMRI studies, stimulating only the central visual field, have reported overall reduced stimulus-evoked activities in the visual cortex in glaucoma patients. However, it remains unknown to what extent the peripheral and central visual function in the visual cortex is altered in glaucoma and how this functional remapping relates to the progression of the disease. Based on our preliminary data, we hypothesize that glaucoma leads to functional remapping of the visual cortex as detected non-invasively by fMRI, and that more abnormal functional and structural neurodegeneration from MRI predicts faster progression of visual field loss in patients at the same clinical stage of glaucoma. The first aim of this study will determine functional and structural changes in the brain of glaucoma patients at different stages of severity in a cross-sectional design. The second aim will elucidate how changes in the brain can help to sub-stratify risk of clinical glaucoma progression in a longitudinal design. The translational impact will be increased by comparing MRI findings with clinical eye exams that include intraocular pressure, visual field perimetry, retinal nerve fiber layer thickness, and dilated fundus photography.